Metoprolol, which has the structural formula ##STR1## is known from e.g. DE-No. 2 106 209. The drug, which is a .beta.-adrenoceptor antagonist has preferably been used as a salt, e.g. the tartrate.
Metoprolol blocks the adrenergic stimulation of the heart and thus reduces the oxygen demand of the cardiac tissue. Apparently, this explains its beneficial effects in angina pectoris and cardioprotective action in myocardial infarction. In addition metoprolol normalizes blood pressure in a large proportion of patients with arterial hypertension which probably is due to an additional action on the control of peripheral resistance to blood-flow.
For patients suffering from cardiovascular disorders it is advantageous to have a constant concentration of the administered drug in the blood. Thus, a controlled release of the drug over a long period of time is desirable. According to the most common treatment, the patients are ordered one fast dissolving tablet twice a day. This gives a varying concentration with high peak and trough values of the drug during the day.
For dosage once a day metoprolol has been incorporated in controlled release tablets of the insoluble matrix type, e.g. Durules.RTM.. However the drug release from the matrix tablets is not satisfying as about 50 percent of the dose is released within a few hours after administration. It has thus been a demand to find a way to obtain a drug preparation having a more constant controlled release of the active component for approximately 20-24 hours, whereby smoother blood concentration and effect profiles will be obtained over the entire dosage interval.
A drug delivery system named Oros.RTM. may be used to obtain a controlled release of e.g. metoprolol for once daily dosage. The system is described in U.S. Pat. No. 4,036,227 and in a supplement to British Journal of Clinical Pharmacology (1985), 19, 695-765 by Theeuwes F. et al. Oros.RTM. is a single-unit system consisting of an osmotically active core composed mainly of the drug substance surrounded by a semipermeable membrane through which a single small opening is drilled. The release of the drug from the system remains constant as long as a steady osmotic pressure is maintained across the membrane. 50-60% of the total content of the drug is released at a constant rate.
In SE-A-8400085 it has been proposed to prepare an enteric coated product, containing e.g. metoprolol, and with slow release of the active compound close to the colon. Such a preparation does not give the constant and slow pH-independent release of metoprolol, which the preparation according to this invention gives.
Depot preparations comprising a large number of smaller units are also known e.g. from EP 13263. This patent describes pharmaceutically indifferent cores covered by the active compound. The cores are made of soluble material e.g. lactose.
There are advantages of a depot preparation comprising a large number of small units, each of which releases the drug at a controlled rate over a depot preparation consisting of one single unit, e.g. a matrix tablet or a tablet surrounded by a coating, which controls the release. It is for example possible to obtain a reproducible emptying of units from the stomach when the particles used are smaller than 1-2 mm. Cf. Bogentoft C. et al.: Influence of food on the absorption of acetylsalicylic acid from enteric-coated dosage forms. Europ J Clin Pharmacol 1978, 14, 351-355. Dispersion over a great area in the gastrointestinal canal gives a more reproducible total time of the passage which is of advantage for the absorption. Cf. Edgar B, Bogentoft C and Lagerstr0m P O: Comparison of two enteric-coated acetylsalicylic acid preparations by monitoring steady-state levels of salicylic acid and its metabolites in plasma and urine. Biopharmaceutics & Drug Disposition 1984, 5, 251-260. In addition a multiple unit preparation is preferable to one single drug unit as the dose is spread out in the intestine. The risk of local irritation and accumulation of several doses due to constriction in the alimentary canal is also considerably lower.
A further advantage with a multiple unit preparation is that it may be divided into smaller portions all having the same absorption properties. This makes it possible to obtain greater flexibility in selecting the size of the dose.